The present invention relates to an improved preservative system for healthcare preparations including ophthalmic solutions, topical gels, creams, rinses and other pharmaceutical applications that utilize an aqueous base and require preservation against microbial contamination. These improved compositions comprise in part a preservative package comprising imidazole and a hydrogen peroxide source. It has been found that this combination of imidazole and hydrogen peroxide have a surprising efficacy against a broad spectrum of bacteria and fungi. Typically preservative combinations known and used in the state of the art are effective against bacteria or fungi, but usually not in combination. The present invention combination preservative package is effective against both fungi and bacteria also exhibits low cytotoxicity and is therefore useful in healthcare applications where said solution is likely to be in contact with tissue in use.
It has been found that at relatively low levels of hydrogen peroxide and imidazole provide activity against both bacteria and fungi, and surprisingly this combination of components forms a preservative package that is more effective against fungi than bacteria. In the state of the art, healthcare solutions, especially ophthalmic solutions have preservative packages that are limited in the ability to control the growth of fungi. Therefore, the state of the art has resorted to higher levels of preservatives to combat this phenomena, often employing long chain quaternary amine compositions or polymeric biguinides, both of which due to their cationic nature tend to bind to the surface of contact lenses or other biomedical devices that are placed in intimate contact with tissue or bodily fluids. Therefore, it would be useful to use a broader spectrum preservative package that would be effective against both bacteria and fungi, and could be used at lower levels than previous preservatives or preservative packages. This invention is not limited to ophthalmic solutions, but is considered to be useful and include healthcare compositions that are intended to clean, preserve, or provide antibacterial or antifungal activity topically.
The present invention relates to an improved preservative package comprised of imidazole, or an imadazole analog and hydrogen peroxide. This preservative package may be used in health care formulation to be applied topically, including ophthalmic care solutions including solutions used ophthalmologically and in contact lens care applications. Specifically in ophthalmic applications, the solutions comprise 0.1 to 5 weight percent of the imidazole or imidazole analog and 5 to 130,000 ppm hydrogen peroxide. These ophthalmic solutions may also include buffering agents, tonicity agents, preservatives, wetting agent, demulcents, surfactants and active pharmaceutical agents as well as the preservative package.
Typically, the imidazole is present at 0.01 to 5weight percent; preferably 0.1 to 0.5 weight percent. The imidazole analogs may chosen from the group consisting of imidazole; bifonazole, butoconazole, chlordantoin, chloroimidazole, cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isocanazole, ketocanazole, lanoconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole, all of which are known in the art.
Buffering Agents
The buffer component which is present in an amount effective to maintain the pH of the liquid medium in the desired range. Among the suitable buffer components or buffering agents which may be employed are those which are conventionally used in contact lens care products. Examples of useful buffer components include those with carbonate functionalities, bicarbonate functionalities, phosphate functionalities, borate functionalities, organic amines, and the like and mixtures thereof The buffers may be alkali metal and alkaline earth metal salts, in particular sodium and potassium chloride.
Tonicity Agents
In order to avoid possible eye irritation, ophthalmic solutions made according to the invention should have an osmolality (a measure of tonicity) of at least about 200 mOsm/kg, preferably in the range of about 200 to about 400 or about 300 mOsm/kg. In an especially useful embodiment, the osmolality or tonicity of the combined liquid medium substantially corresponds to the tonicity of the fluids of the eye, in particularly the human eye.
Any suitable ophthalmically acceptable tonicity component or components may be employed, provided that such component or components are compatible with the other ingredients of the combined liquid medium and do not have deleterious or toxic properties which could harm the eye. Examples of useful tonicity components include sodium chloride, potassium chloride, mannitol, dextrose, glycerin, propylene glycol and mixtures thereof. In one embodiment, the tonicity component is selected from inorganic salts and mixtures thereof. It is preferred that the tonicity of the ophthalmic solutions not depend upon sodium chloride to the extent possible.
The amount of ophthalmically acceptable tonicity component utilized can vary widely. In one embodiment, the tonicity component is preferably present in the combined liquid medium in an amount in the range of about 0.1 to about 0.9% w/v of the combined liquid medium.
Other Agents
Examples of such additional components include cleaning agents, wetting agents, nutrient agents, sequestering agents, viscosity builders, contact lens conditioning agents, colorants, and the like. These additional components may each be included in the combined liquid medium in an amount effective to impart or provide the beneficial or desired property to the combined liquid medium. Such additional components may be included in the presently useful liquid media in amounts similar to the amounts of such components used in other, e.g., conventional, contact lens care products.
Examples of useful sequestering agents include disodium ethylene diamine tetraacetate, alkali metal hexametaphosphate, citric acid, sodium citrate and mixtures thereof Viscosity builders include hydroxyethyl cellulose, hydroxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol and mixtures thereof
Enzymes
The present invention may also further include enzymes useful in cleaning contact lenses. These enzymes include, but are not necessarily limited to, peroxide-active enzymes which are conventionally employed in the enzymatic cleaning of contact lenses. For example, many of the enzymes disclosed in Huth et al U.S. Reissue Pat. No. 32,672 and Karageozian et al U.S. Pat. No. 3,910,296 are useful in the present invention. These patents are incorporated in their entirety by reference herein. Among the useful enzymes are those selected from proteolytic enzymes, lipases and mixtures thereof Preferred proteolytic enzymes are those which are substantially free of sulfhydryl groups or disulfide bonds, whose presence may react with the active oxygen in the HPLM to the detriment of the activity of the enzyme. Metallo-proteases, those enzymes which contain a divalent metal ion such as calcium, magnesium or zinc bound to the protein, may also be used.